Learning and memory requires multiple forms of synaptic plasticity mediated by mGlu, NMDA, AMPA glutamate receptors (mGluR, NMDAR, AMPAR). These plasticity mechanisms include long-term potentiation (LTP) and depression (LTD), that rapidly increase or decrease synaptic strength of specific inputs, and homeostatic synaptic scaling, which scale-up or -down strength of all inputs. Importantly, alterations in LTP/LTD and homeostatic plasticity are associated with cognitive dysfunction in animal models of nervous system disorders. Until recently, the signaling mechanisms controlling AMPARs during LTP/LTD and homeostatic plasticity were envisioned as distinct. However, LTP/LTD and homeostatic plasticity can both result in synaptic incorporation of high-conductance, Ca2+-permeable AMPA receptors (CP-AMPAR) containing GluA1, but lacking GluA2, subunits that not only impact synaptic strength but also alter plasticity itself - i.e. metaplasticity. Nevertheless, the roles of CP-AMPARs in controlling plasticity in hippocampal neurons are controversial. A major barrier to moving the field forward has been that we do not have an adequate understanding of the signaling mechanisms that control CP-AMPARs. Importantly, recent studies from our laboratory employing knock-in mice demonstrated that the kinase PKA and phosphatase Calcineurin (CaN) anchored to A-kinase anchoring protein (AKAP) 79/150 play opposing roles regulating GluA1 phosphorylation to control both basal and plasticity-regulated CP-AMPAR synaptic incorporation at hippocampal synapses. In particular, we found that AKAP-PKA/CaN positive/negative regulation of CP-AMPAR synaptic incorporation controls LTP/LTD balance and determines whether synapses can undergo homeostatic potentiation. In addition, we found that palmitoylation/depalmitoylation of the AKAP N-terminal targeting domain controls AKAP delivery/removal from dendritic spines in coordination with cellular correlates of LTP/LTD. Furthermore, recent unpublished work indicates that knock-in disruption of AKAP palmitoylation in vivo increases basal CP-AMPAR activity to prevent subsequent LTP. Finally, both published and unpublished data indicate that these CP- AMPAR-mediated changes in plasticity are influenced by developmental age, induction stimulus, and crosstalk with CaMKII and mGlu1 signaling suggesting engagement of metaplasticity. Here we will use the unique knock-in mice we developed to test the overall hypothesis that regulation of AKAP postsynaptic targeting by palmitoylation (aim 1) and CaMKII signaling (aim 2), and interactions between AKAP-PKA/CaN and mGluR signaling (aim 3) control LTP/LTD balance at CA1 synapses through CP-AMPAR-mediated metaplasticity.